Candidate genes for obesity and related phenotypes

by Swarbrick, Michael

Abstract (Summary)

The current epidemic of obesity poses a substantial threat to public health worldwide. Obesity is associated with many deleterious health conditions, including type 2 diabetes, hypertension, dyslipidaemia, respiratory conditions, arthritis, and some forms of cancer. Moreover, the rising prevalence of obesity has been accompanied by a substantial increase in the cost of treating these conditions. Obesity results from a complex interaction between behavioural, environmental, and genetic factors. While the recent increase in the prevalence of obesity is largely due to behavioural factors (for example, physical inactivity); it has also been observed that genetic factors make a large contribution to individual susceptibility. In fact, studies indicate that as much as 50 - 80% of the variation in measures of obesity can be attributed to the effects of genes. Furthermore, closer examination of this genetic component using segregation analysis has indicated the presence of common genes for obesity, with large effects on the phenotype. However, these putative major genes for obesity have not yet been identified. The aim of this thesis was to investigate the role of three distinct genetic loci in obesity and related cardiovascular factors, including type 2 diabetes and dyslipidaemia. The aim of the first investigation was to test whether a common polymorphism (Pro12Ala) in the gene encoding peroxisome proliferator-activated receptor gamma 2 (PPAR-?2) was associated with obesity and other cardiovascular risk factors in a large group of Caucasian subjects. PPAR-?2 is an adipogenic transcription factor, which also regulates insulin sensitivity in adipose tissue. No association was observed between the Pro12Ala polymorphism and obesity in Caucasians, but obese subjects carrying the Ala allele displayed an altered blood lipid profile compared with obese Pro/Pro subjects. As the Pro12Ala polymorphism may exacerbate the risk of cardiovascular disease by modifying blood lipid profile in obesity, this relationship was examined further in a separate population. The aim of the second investigation was to determine whether the Pro12Ala polymorphism was associated with obesity, dyslipidaemia, diabetes and carotid intima-medial wall thickening in a population at high risk of developing cardiovascular disease. Australian Aboriginal people display high rates of mortality from cardiovascular disease, and it is possible that their increased susceptibility is due to genetic factors. However, the results from the Aboriginal population confirmed the results of the first study: there was no intrinsic association between the Pro12Ala variant and obesity. In addition, the Ala allele was not associated with deleterious changes in blood lipid profile, as it was in Caucasians. The aim of the third investigation was to confirm the presence of a quantitative trait locus (QTL) for obesity on chromosome 20q13. Highly polymorphic genetic markers in this region were tested for linkage and association with several measures of obesity in a Caucasian population. None of the measures of obesity were linked to or associated with markers spanning 20q13, suggesting that this chromosomal region does not contain a major locus for obesity in this Caucasian population. In the fourth investigation, the 5' sequence of Agouti Signalling Protein (ASIP) was identified. ASIP is a candidate gene for obesity, as it is expressed at high levels in adipocytes, and may participate in several obesity-related processes. Three new exons and two alternative promoters were identified for the ASIP gene. These results may lead to greater understanding of the role of ASIP in obesity and adipocyte metabolism; and may also be used to direct further research into genetic variation within this candidate gene. In conclusion, extensive study of two established candidate genetic loci revealed no association with measures of obesity. Therefore, it is likely that loci other than these make significant contributions to obesity in humans. Further investigation of novel candidate genes, such as ASIP, may allow the identification of novel genetic polymorphisms and new pathways important for the genetic basis of obesity.